Coverage Policy Manual
Policy #: 2022011
Category: Laboratory
Initiated: March 2022
Last Review: March 2024
  Genetic Test: Testing for Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusions

Description:
The neurotrophic receptor tyrosine kinase (NTRK) gene fusions are uncommon kinase fusion events that drive tumorigenesis in a small fraction of solid tumors, regardless of tissue type. The tropomyosin receptor kinases (TRK) proteins A, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3 respectively. In healthy tissue, the TRK pathway is involved in the development and functioning of the nervous system as well as cell survival. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that are oncogenic, promoting tumor cell proliferation and their survival.

Policy/
Coverage:
For NTRK gene fusion testing for targeted therapy in non-small cell lung cancer see coverage policy 2015002.
 
Effective July 1, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Targeted molecular testing for NTRK1/2/3 fusions meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when there is documentation in the medical record that the use of this testing will lead to a change in therapy that has been confirmed to result in improved net health outcome(s) for one of the following indications:
 
    1. In tumors where NTRK fusions have a frequency of approximately 10% or greater (including but not limited to the following):
 
      • Infantile fibrosarcoma;
      • Cellular congenital mesoblastic nephroma;
      • Secretory breast cancer;
      • Mammary secretory carcinoma of the salivary gland;
      • Spitzoid melanoma;
      • Metastatic papillary thyroid cancer;
      • Analog pediatric high-grade glioma; or
      • GIST when no KIT/PDGFRA/RAS pathogenic or likely pathogenic (P/LP variant) is identified).
 
OR
 
2. In solid tumors of smooth muscle, testes, or neural tissue when all of the following criteria are met:
      • Standard treatment options have been exhausted with continued progression of cancer, AND
      • Tumor type has been shown to respond to treatment with an FDA approved medication for this biomarker
 
OR
 
3. In solid tumors known to respond to treatment with an FDA approved medication for this biomarker with positive NTRK IHC results or IHC is not possible for molecular confirmation.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of NTRK genetic testing for any other indication or condition does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of NTRK genetic testing for any other indication or condition is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
The annual incidence of NTRK fusion-driven tumors is estimated to be 1500-5000 cases in the United States.  NTRK fusions may be more characteristic of rare cancers such as mammary analogue secretory carcinoma, secretory breast carcinoma, or infantile fibrosarcoma, the incidence of NTRK fusions is below 1% for most common cancers such as lung, prostate, and colon cancer.
 
Metastatic (failed prior therapy) and/or unresectable solid tumors are rarely curable and generally have a poor prognosis.  According to the American Cancer Society, the estimated 5-year survival rates for metastatic breast, colon, lung, and melanoma are 22%, 12%, 1%, and 15-20%, respectively.  The likelihood of achieving a response to second-line or greater therapy is less than 50%; in the case of colon and non-small-cell lung cancer, much less than 50%. There is no information regarding the effects of NTRK gene fusions on prognosis, either favorable or unfavorable.
 
Although there are multiple FDA approved treatments for many common adult cancers that rarely have an NTRK fusion, such as lung, prostate, and colon cancer, there were no drugs approved specifically for patients with metastatic or unresectable solid tumors harboring an NTRK fusion prior to the approval of recent agents (e.g. larotrectinib and entrectinib). Additionally, there are no approved treatments specific for mammary analogue secretory carcinoma, secretory breast carcinoma, and infantile fibrosarcoma, which frequently harbor NTRK fusions. Moreover, in some cases where resection is a potentially curative approach, surgery can result in unacceptable morbidity such as limb amputation (e.g., in some patients with infantile fibrosarcoma).
 
The FDA has granted accelerated approval for larotrectinib (Vitrakvi). The drug is indicated for adult and pediatric patients with solid tumors positive for a neurotrophic receptor tyrosine kinase (NTRK1, NTRK2, or NTRK3) gene fusion. These patients should have no known acquired resistance P/LP variant, and they must have metastatic disease or an unresectable tumor where the risk of surgery is high, and no other alternative therapeutic options exist.
 
The data to support the approval of larotrectinib is sparse. The FDA notes continued approval will be contingent on further evidence development. Notably, 6 of 55 (11%) patients in these studies did not respond to larotrectinib. Of these six, three had follow up tumor testing using a pan-TRK IHC assay which was negative and did not confirm evidence of the initial fusion event. It is unclear whether these cases represent false positive NGS test results or whether the gene fusion was present but not actively expressed.
 
Three multicenter, open-label, single-arm clinical trials:  phase 1 Study of the oral TRK Inhibitor Larotrectinib in adult patients with solid tumors study (LOXO-TRK-14001; NCT02122913).  A Phase 1/2 Study of the oral TRK inhibitor LOXO-101 in pediatric patients with advanced solid or primary CNS tumors (SCOUT; NCT02637687), and a phase 2 basket study of the oral TRK inhibitor larotrectinib in subjects with NTRK fusion-positive tumors (NAVIGATE; NCT02576431) evaluated larotrectinib in pediatric and adult patients with unresectable or metastatic solid tumors.  Drilon et al reported the pooled analysis of the first 55 consecutive patients at the primary data cutoff date of July 17, 2017 (Drilon, 2018).  Subsequent to the publication of these results, Lassen et al presented more recent data with a primary data cutoff date of July 30, 2018, as an abstract (data not shown) (Lassen, 2018). All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The major efficacy outcome measures were ORR and duration of response (DOR), as determined by a blinded independent review committee according to RECIST v1.1. The enrolled patient population encompassed 12 different types of cancers with the most common being soft tissue sarcoma (20%), salivary gland (22%) and infantile fibrosarcoma (13%). The median age was 45 years (range 4 months to76 years), 53% male, 67% White, and 93% had an Eastern Cooperative Oncology Group performance status from 0 to 1 (93%). Eighty-two percent of patients had metastatic disease and 18% had locally advanced unresectable disease.
 
Patients were heavily pre-treated—98% had received prior treatment for their cancer, including surgery, radiotherapy, or systemic therapy. Of these, 82% received a median of 2 prior systemic regimens and 35% received 3 or more prior systemic regimens. The most common cancers were salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). A total of 50 patients had NTRK gene fusions detected by next-generation sequencing and 5 patients had NTRK gene fusions detected by fluorescence in situ hybridization.
 
Three, single-arm studies evaluating the efficacy of larotrectinib in 144 pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion are ongoing. Pooled results of the first 55 sequentially enrolled patients have been published. All patients were required to have progressed on systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. The ORR by the Institutional Review Committee (primary study endpoint) was 75% (95% confidence interval 61 to 85); complete response 13% and partial response 62%. Responses observed were independent of age, tumor type, NTRK gene or fusion partner. The median time to response was 1.8 months (range 0.9 to 6.4) with 76% responses occurring within 2 months.
 
The clinical development program to assess the efficacy of entrectinib for individuals with NTRK fusion-positive, locally advanced or metastatic solid tumors consists of an integrated analysis of the Phase II Basket Study of Entrectinib for the treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK gene rearrangements (STARTRK-2), Phase I multicenter, open-label study of oral entrectinib (RXDX-101) in adult patients with Locally Advanced or Metastatic Cancer Confirmed to be Positive for NTRK1, NTRK2, NTRK, ROS1, or ALK Molecular Alterations (STARTRK-1) and Phase I Study of entrectinib-An Oral Pan-TRK, ROS1, and ALK Inhibitor in patients With Advanced Solid Tumors With Relevant Molecular Alterations (ALKA-372-001) trials. The integrated analysis included data of 54 patients with NTRK fusion-positive solid tumors. Majority of patients in the NTRK fusion-positive solid tumors (95%) were from STARTRK-2 trial. Results available from prescribing label were used for the evidence review.
 
The median age was 57.5 years (range, 21 to 83 years), 89% had an ECOG performance score of 0 or 1, 89% had received prior anticancer therapy (20% received 1, 43% received 2) and 22.2% had CNS disease at baseline.  In 54 patients with NTRK fusion-positive solid tumors, the objective response rate was 57.4% and median DOR was 10.4 months. Due to the small sample size, there is a degree of uncertainty regarding the magnitude of the treatment effect of entrectinib in any single histologic subtype of solid tumors with an activating NTRK fusion.  The safety population included 355 adult patients with locally advanced or metastatic solid tumors harboring NTRK1/2/3, ROS1, and ALK gene rearrangements treated with entrectinib across 3 clinical studies with a median duration of exposure to entrectinib of 5.5 months. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Serious adverse reactions were reported in 38.6% of patients; most frequently (>2%) reported serious adverse reactions were pneumonia, dyspnea, and pleural effusion. Permanent discontinuation due to adverse events occurred in 8.5% of patients while discontinuation due to treatment-related adverse events occurred in 3.9% of patients. Assessment of a causal relationship between entrectinib and adverse events is limited due to the single-arm design of the study.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81191NTRK1 (neurotrophic receptor tyrosine kinase 1) (eg, solid tumors) translocation analysis
81192NTRK2 (neurotrophic receptor tyrosine kinase 2) (eg, solid tumors) translocation analysis
81193NTRK3 (neurotrophic receptor tyrosine kinase 3) (eg, solid tumors) translocation analysis
81194NTRK (neurotrophic tropomyosin receptor tyrosine kinase 1, 2, and 3) (eg, solid tumors) translocation analysis

References: Doebele RC, Drilon A, Paz-Ares L, et al.(2020) Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. Feb 2020; 21(2): 271-282. PMID 31838007

Drilon A, Laetsch TW, Kummar S, et al.(2018) Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. Feb 22 2018; 378(8): 731-739. PMID 29466156

Hechtman JF.(2022) NTRK insights: best practices for pathologists. Mod Pathol. 2022 Mar;35(3):298-305. doi: 10.1038/s41379-021-00913-8. Epub 2021 Sep 16. PMID: 34531526; PMCID: PMC8860742.

Hong DS, Bauer, et al.(2019) Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb;30(2):325-331. doi: 10.1093/annonc/mdy539. Epub 2019 Dec 24.

Hong DS, DuBois SG, Kummar S, et al.(2020) Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. Apr 2020; 21(4): 531-540. PMID 32105622

Kheder ES, Hong DS.(2018) Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. Clin Cancer Res. Dec 01 2018; 24(23): 5807-5814. PMID 29986850

Marchiò C, Scaltriti M, Ladanyi M, et al.(2019) ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019 Sep 1;30(9):1417-1427. doi: 10.1093/annonc/mdz204.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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